Synthesis of Spiro Oxazolidinedione Analogues Based on Tandem Multicyclizations of 1,3-Dimethylalloxan and Enaminones in Water

Abstract

A tandem double-annulation reaction of 1,3-dimethylalloxan with enaminones, generated in situ from alkyl amines and alkyl but-2-ynoates or pent-3-yn-2-ones to give functionalized oxazolidinedione spiro analogues is described. Three of the four carbonyl groups of alloxan have been engaged through a tandem Michael addition, aldol-type condensation, and double intramolecular annulation sequence.

Key words

alloxan - enaminones - multicomponent reaction - oxazolidinediones - spiroheterocycles - tandem reaction

Publication History

Received: 27 September 2020

Accepted after revision: 11 November 2020

Accepted Manuscript online:
11 November 2020

Article published online:
08 December 2020

• References and Notes

• 1a Yang C, Shen HC, Wu Z, Chu HD, Cox JM, Balsells J, Crespo A, Brown P, Zamlynny B, Wiltsie J, Clemas J, Gibson J, Contino L, Lisnock JM, Zhou G, Garcia-Calvo M, Bateman T, Xu L, Tong X, Crook M, Sinclair P. Bioorg. Med. Chem. Lett. 2013; 23: 4388
• 1b Clark-Lewis JW. Chem. Rev. 1958; 58: 63
• 2a Shev EE. Calif. Med. 1972; 117: 62
• 2b Purohit SS, Kumar D. All Results Journal: Chem. 2014; 5: 1 http://arjournals.com/index.php/Chem/article/download/83/85 (accessed Dec 1, 2020)
• 3 Harada K, Kubo H, Tanaka A, Nishioka K. Bioorg. Med. Chem. Lett. 2012; 22: 504
• 4 Molineux RJ. Alkaloids: Chemical and Biological Perspectives, Vol. 5. Pelletier SW. Wiley; New York: 1987. Chap. 1
• 5a Singh GS, Desta ZY. Chem. Rev. 2012; 112: 6104
• 5b Galliford CV, Scheidt KA. Angew. Chem. Int. Ed. 2007; 46: 8748
• 5c Pajouhesh H, Parsons R, Popp FD. J. Pharm. Sci. 1983; 72: 318
• 6a Das S, Chandrasekhar S, Yadav JS, Grée N. Chem. Rev. 2001; 107: 3286
• 6b Seemann M, Schöller M, Kudis S, Helmchen G. Eur. J. Org. Chem. 2003; 2122
• 6c Hong AY, Krout MR, Jensen T, Bennett NB, Harned AM, Stoltz BM. Angew. Chem. Int. Ed. 2011; 50: 2756
• 6d Kim KH, Miller MJ. Tetrahedron Lett. 2003; 44: 4571
• 6e Chebib M, Duke RK, Allan RD, Johnston GA. R. Eur. J. Pharmacol. 2001; 430: 185
• 6f Liu G, Shirley ME, Van K N, McFarlin RL, Romo D. Nat. Chem. 2013; 5: 1049
• 7a Trost BM, Pinkerton AB. J. Org. Chem. 2001; 66: 7714
• 7b Roche SP, Aitken DJ. Eur. J. Org. Chem. 2010; 5339
• 8a Schank K, Lieder R, Lick C, Glock R. Helv. Chim. Acta 2004; 87: 869
• 8b Teimouri MB, Abbasi T. Tetrahedron 2010; 66: 3795
• 8c Teimouri MB, Abbasi T, Ahmadian S, Poor Heravi MR, Bazhrang R. Tetrahedron 2009; 65: 8120
• 8d Ahadi S, Abaszadeh M, Khavasi HR, Bazgir A. Tetrahedron 2012; 68: 2906
• 8e Teimouri MB, Asnaashari B. Tetrahedron Lett. 2014; 55: 2249
• 9a Xue L.-Y, Jiang B, Tu M.-S, Tu S.-J. Tetrahedron Lett. 2012; 53: 6611
• 9b Rubin MB, Gleiter R. Chem. Rev. 2000; 100: 1121
• 9c Singh R, Geetanjali Geetanjali. Synthesis 2005; 2315
• 9d Kaupp G, Naimi-Jamal MR. Eur. J. Org. Chem. 2002; 1368
• 10a Teimouri MB, Abbasi T, Mivehchi H. Tetrahedron 2008; 64: 10425
• 10b Teimouri MB, Abbasi T, Khavasi HR. J. Chem. Res. 2010; 40: 310
• 11 Spiro Compounds 4 and 5: General ProcedureA mixture of the appropriate amine 1 (1 mmol) and alkyne 2 (1 mmol) in H₂O (5 mL) was stirred at r.t. for 3 h. 1,3-Dimethylalloxan (3; 1 mmol) was then added, and the mixture was stirred for 24 h at r.t. until the reaction was complete (TLC). The H₂O was removed by using a rotary evaporator, and the residue was purified by column chromatography [silica gel, hexane–EtOAc (5:1)].Methyl (2E)-(3,7-Dimethyl-2,4,6-trioxo-1-oxa-3,7-diazaspiro[4.4]non-8-ylidene)acetate (4a)Colorless amorphous powder; yield: 0.196 g (73%); mp 200–202 °C (dec.); R_f = 0.55 (25% EtOAc–hexane). IR (KBr): 3090 (=C–H), 1836, 1745, 1743 and 1699 (C=O), 1638 (C=C) cm^–1. ¹H NMR (300.1 MHz, CDCl₃): δ = 3.13 (s, 3 H, NCH₃), 3.16 (s, 3 H, NCH₃), 3.73 (OCH₃, 3 H), 3.55 and 3.90 (d of AB-system, ² J _HH = 19.3, ⁴ J _HH = 1.8 Hz, 2 H, CH₂), 5.43 (t, ⁴ J _HH = 1.8 Hz, 1 H, =CH). ¹³C NMR (75.5 MHz, CDCl₃): δ = 169.5, 166.8, 166.5, 153.9, 152.4, 95.4, 82.4, 51.5, 33.5, 28.3, 26.8. Anal. Calcd for C₁₁H₁₂N₂O₆ (268.23): C, 49.26; H, 4.51; N 10.44. Found: C, 49.47; H, 4.57; N, 10.37.Methyl 3-Methyl-2,4,6-trioxo-8-piperidin-1-yl-1-oxa-3-azaspiro[4.4]non-7-ene-7-carboxylate (5a)Colorless powder; yield: 0.200 g (62%); mp 193–195 °C (dec.); R_f = 0.50 (25% EtOAc–hexane). IR (KBr): 1816, 1727, 1701 and 1667 (C=O), 1592 (C=C) cm^–1. ¹H NMR (300.1 MHz, CDCl₃): δ = 1.79 (m, 6 H, CH₂CH₂CH₂), 3.01 and 3.24 (AB-system, ² J _HH = 16.6 Hz, 2 H, CH₂), 3.12 (s, 3 H, NMe), 3.54 (m, 4 H, CH₂NCH₂), 3.82 (s, 3 H, OMe). ¹³C NMR (75.5 MHz, CDCl₃): δ = 185.7, 170.9, 170.3, 164.3, 154.4, 103.7, 85.4, 53.2, 51.5, 50.7, 35.7, 26.0, 25.9, 25.2, 23.0. Anal. Calcd for C₁₅H₁₈N₂O₆ (322.32): C, 55.90; H, 5.63; N, 8.69; Found: C, 56.17; H, 5.60; N, 8.76.
• 12 CCDC 2034055 contains the supplementary crystallographic data for 4a. These data can be obtained free of charge from the joint CCDC/FIZ Karlsruhe deposition service via www.ccdc.cam.ac.uk/getstructures
• 13 Tajaddini N, Talebizadeh M, Anary-Abbasinejad M. Tetrahedron Lett. 2019; 60: 366
• 14 Xia Y, Huang H, Zhang F, Deng G.-J. Org. Lett. 2019; 21: 7489